This invention relates to C-substituted pentacycloazoles containing heteroatoms in the 2, 3 and 5 positions of the pentacycloazole ring and N-substituted pentacycloazoles containing nitrogen atoms in either the 2 and 4 positions or in the 3 position of the pentacycloazole ring.
Ellingboe et al. state in the J. Med. Chem., Vol. 36, pages 2485-2493 (1993), which is hereby incorporated by reference, that drugs currently available for the control of the hyperglycemia associated with type 2 (non-insulin dependent) diabetes mellitus possess significant liabilities or efficacy limitations and that considerable effort has been directed toward the development of novel, orally active antihyperglycemic drugs. They also state that many of these new compounds incorporate a relatively acidic heterocycle which serves as the pharmacophore responsible for antihyperglycemic activity, such as thiazolidine-2,4-dione, tetrazole and oxazolidine-2,4-dione rings. In an earlier paper, J. Med. Chem. Vol. 35, pages 1176-1183 (1992), which is hereby incorporated by reference, Ellingboe et al. described a number of antihyperglycemic agents, which contain an acidic 3H-1,2,3,5-oxathiadiazole 2-oxide ring, appended via a methylene bridge to numerous aromatic systems. Kangi et al. E.P. 177, 353, which is hereby incorporated by reference, disclose antihyperglycemic thiazolidine pharmacophore appended via a methylene bridge to suitable aromatic systems.
The general object of this invention is to provide new antihyperglycemic compounds based on new pharmacophores. Other objects appear hereinafter.
In one aspect, this invention is an antihyperglycemic compound selected from the group consisting C-substituted pentacycloazole pharmacophore containing heteroatoms in the 2, 3 and 5 position of the pentacycloazole ring and N-substituted pentacycloazole pharmacophore containing nitrogen atoms in a position selected from the group consisting of the 2 and 4 positions of the pentacycloazole ring and the 3 position of the pentacycloazole ring.
In a second aspect, this invention is an antihyperglycemic composition comprising a pharmaceutically acceptable carrier, diluent or excipient and an effective amount of an antihyperglycemic compound selected from the group consisting C-substituted pentacycloazole pharmacophore containing heteroatoms in the 2, 3 and 5 position of the pentacycloazole ring and N-alkyl substituted pentacycloazole pharmacophore containing nitrogen or other hereto atoms in a position selected from the group consisting of the 2 and 4 positions of the pentacycloazole ring and the 3 position of the pentacycloazole ring.
In a third aspect, this invention is a method of reducing the hyperglycemia associated with non-insulin dependent diabetes mellitus which method comprises orally administering to a mammal, such as a human, a therapeutic dose of an antihyperglycemic compound selected from the group consisting C-substituted pentacycloazole pharmacophore containing heteroatoms in the 2, 3 and 5 position of the pentacycloazole ring and N-substituted pentacycloazole pharmacophore containing nitrogen atoms in a position selected from the group consisting of the 2 and 4 positions of the pentacycioazole ring and the 3 position of the pentacycloazole ring.
We have now found that the objects of this invention can be attained with antihyperglycemic compounds having a C-substituted pentacycloazole pharmacophore containing heteroatoms in the 2, 3 and 5 position of the pentacycloazole ring or an N-alkyl-substituted pentacycloazole pharmacophore (where the alkyl group has 1 to 12 carbon atoms) containing nitrogen atoms in both the 2 and 4 positions or in the 3 position of the pentacycloazole ring wherein the pentacycloazole ring is linked to a suitable aromatic system utilized with pharmacophores responsible for antihyperglycemic activity by an aliphatic group of 1 to 2 carbon atoms and a carbon atom of said aliphatic group is bonded directly to the pentacycloazole ring. Our studies have shown that other things being equal, many other compounds containing different pentacycloazole moleties, lack the antihyperglycemic activity of the compounds of this invention. Further, it appears that if the pentacycloazole moiety is linked to the same aromatic system by an isomeric aliphatic group having no carbon atom bonded to the pentacycloazole ring, the compound lacks antihyperglycemic activity. For example, when a --CH.sub.2 --S-- linker was employed, the compound was inactive when the "S--" part of the linker was bonded to a C-pentacycloazole moiety and active when the "CH.sub.2 --" part of the linker was bonded to a C-pentacycloazole moiety. Likewise, when the pharmacophore was bonded directly to the aromatic moiety without an aliphatic linking group, the compounds were inactive.
While Mullican et al. in the J. Med. Chem., Vol. 36, pages 1090-1099 (1993) disclose a C-substituted-2,3,5-triazole linked through methylene to a 4-hydroxy-3,5-dibutylphenyl moiety at page 1091 and Boschelli et al. in J. Med. Chem., Vol. 36, pages 1802 to 1810 (1993) disclose a C-substituted pentacycloazole containing heteroatoms in the 2, 3 and 5 position linked through methylene to a dichlorophenylaminophenyl group moiety at page 1804, neither article describes or suggests that the compounds have antihyperglycemic activity. Further, to the best of our knowledge neither the 4-hydroxy-3,5-dibutylphenyl moiety nor the dichlorophenylaminophenyl group have been used with pharmacophores responsible for antihyperglycemic activity.
The compounds of this invention can be represented by the structure EQU Ar--(G).sub.n-1 --(CH.sub.2).sub.m-1 --CH.sub.2 Z
The bond of attachment to Z is assigned number 1 as described in the following schematic structure formula (I): ##STR1## where each Q is independently C, N, O, or S as described in the following definition of Z.
Z is a C-substituted pentacycloazole containing heteroatoms in the 2, 3 and 5 positions of the pentacycloazole ring or an N-substituted (N at position 1) pentacycloazole containing N atoms in either the 2 and 4 positions or in the 3 position of the pentacycloazole ring; G is oxygen or sulfur; m and n are whole numbers ranging from 1 to 2; and Ar is a suitable aromatic system.
In somewhat greater detail, Z can have any of the structures inclusive of double bond tautomeric forms as follows: ##STR2## wherein X.sub.1 is O or S; X.sub.2 is --SR; and each R is independently selected from H, methyl, ethyl, propyl and butyl.
Ar can be any suitable aromatic system utilized with other pharmacophores responsible for antihyperglycemic activity such as those disclosed in the aforesaid Ellingboe et al. articles; the aforesaid Kangi et al. E.P. 177, 353; Momose et. al. in Chem. Pharm. Bull., Vol. 39, No. 6 at pages 1440 to 1445 (1991); Cantello et al. E.P. 415605; Clark et al. U.S. Pat. No. 4,791,125; Kees U.S. Pat. No. 5,183,825; Goldstein et al. WO 93/00343; Hindley E. P. 306,228 all of which are hereby incorporated by reference. Accordingly, the aromatic systems can range from simple dihydronaphthalene moleties in U.S. Pat. No. 5,183,825 to aromatic rings linked to heterocylic rings.
The preferred aromatic systems can be represented by the structure: EQU Y--(CH.sub.2).sub.p --(G')--Ar'--
wherein Ar' is a divalent arylene moiety, such as phenylene, methyl substituted phenylene, chlorophenylene, etc.; G' is O or S; and Y is a cycloalkyl ring, such as methylcyclohexyl, a substituted or unsubstituted aryl group or a heterocyclic such as 2-phenyl-4-oxazolyl; p is a number from 1 to 6. An illustrative Y group is shown in formula (II): ##STR3##
As is demonstrated in the Examples, the various C-substituted pentacycloazole compounds of this invention can be prepared by routine techniques. For example, C-substituted 2,3,5-triazoles can be prepared by reacting ##STR4##
A C-substituted 2,3-diazole can be prepared by reacting ArCH.sub.2 CO.sub.2 R+Hydrazine hydrate followed by cyclization with CS.sub.2.
A C-substituted 2,5-diazole can be prepared by reacting ArCH.sub.2 CN+CH.sub.3 OH+HCl to form ArC(.dbd.NH.sub.2)OCH.sub.3.sup.+ Cl.sup.- followed by Na in CH.sub.3 OH to form an amidoxime and then treating with carbonyldiimidazole.
A C-substinuted-1,3,4-oxathiazolin-5-one can be prepared by converting ##STR5## to the amide followed by cyclization with chlorocarbonylsulfenyl chloride.
A C-substituted 1,2,4-thiadiazolin-5-one can be prepared by reacting ArC(.dbd.NH.sub.2)OCH.sub.3.sup.+ Cl.sup.- described above with sodium hydride and cyclizing with chlorocarbonylsulfenyl chloride.
A N-substituted azole can be prepared either by reaction route (1) or (2) below:
(1) Reacting ArCHO with semicarbazide hydrochloride followed by reduction with boron hydride and cyclizing with carbonyldiimidazole or; PA1 (2) Reacting ArCH.sub.2 NH.sub.2 with sodium cyanate and cyclizing with diethyl oxylate.
The compounds of this invention and salts thereof exhibit excellent blood-glucose and blood-lipid lowering actions in mammals (e.g., mouse, rat, dog, cat, monkey, horse, and human beings), and show a low degree of toxicity in terms of both acute and subacute toxicities. Therefore, the compounds and salts thereof are of value to human beings for the treatment of hyperlipemia, diabetes and their complications.
The compounds of this invention are generally compounded with "pharmaceutically acceptable" carriers, diluents or excipients, which are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg no about 50 mg/kg of body weight of an active compound of this invention. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. The compound can be administered by a variety of routes although oral is greatly preferred.
Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compounds of the invention together with a pharmaceutically acceptable carrier or diluent therefor. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
The active ingredient can also be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.